Strategies for promoting healthy brain aging and preventing Alzheimer's disease (AD) are increasingly important with the increasing prevalence of AD. Animal data suggests exercise may modify the AD neuropathological burden in mouse models of the disease while human studies of normal aging suggest exercise may protect against age-related functional and structural brain changes. Despite these studies, limited evidence exists on the role of exercise in AD and there is a need for rigorous, well-designed trials to assess the benefits of exercise in AD. Our overall hypothesis is that enhanced aerobic fitness will slow the progression of AD. We propose to examine this hypothesis in a randomized, controlled trial of 26 weeks of aerobic exercise vs. stretching (control group) in individuals with early-stage AD. Exercise training will occur in a community setting through the local network of Greater Kansas City YMCAs, building on our group's history of NIH-funded collaborations with the YMCA network. The overall objective of the proposed pilot trial is to inform and advance the design of a subsequent full- scale clinical trial, consistent with the funding announcement Alzheimer's Disease Pilot Clinical Trials (PAR-07- 142). We will meet this objective through two primary aims designed to generate preliminary efficacy data on aerobic fitness in AD and two additional exploratory aims assessing disease-modifying benefits and potential mechanisms relating aerobic fitness with brain health. Aim 1 will test the hypothesis that enhanced aerobic fitness will provide cognitive benefits to individuals in the earliest clinical stages of AD while aim 2 will assess whether enhanced aerobic fitness has functional and behavioral benefits. The exploratory aims are designed to 1) refine neuroimaging measures assessing disease-modifying effects of exercise and, 2) examine potential underlying mechanisms (such as anabolic and inflammatory markers) relating fitness with brain health. The current project is a natural extension of a programmatic line of investigation developed by the KU Alzheimer and Memory Program. This pilot clinical trial will inform and advance the design of a subsequent full scale clinical trial while providing important data to explore the effect, and potential underlying mechanisms, of aerobic exercise on brain health in the earliest clinical stages of AD. There is a need for rigorous data demonstrating and defining the efficacy of exercise in AD. This would not only have an impact on public health policy in encouraging the public to adapt more active lifestyles, it would also stimulate the development of effective exercise delivery programs for individuals with AD. PUBLIC HEALTH RELEVANCE: Strategies for promoting healthy brain aging and preventing Alzheimer's disease (AD) are increasingly important with the unprecedented growth of the elderly population and subsequent increase in the prevalence of AD. There is a need for rigorous, well-designed trials to more precisely define the role of exercise in AD. Demonstrating and defining the efficacy of exercise in AD would not only have an impact on public health policy in encouraging the public to adapt more active lifestyles, it would also stimulate the development of effective exercise delivery programs for individuals with AD.